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Disease at the Cellular Level

THE NEXTDDS

Abstract

Cellular and molecular biologists have been uncovering the
mechanisms by which plants and animals attempt to maintain their function at a
cellular level. As cells age they need to be replaced or the organism would eventually
die. The process of cellular death and rebirth is a tightly regulated process
seen in the simplest of multicellular organisms, and dysfunction of that
process can quickly lead to death. Programmed cell death is a
genetically-controlled, locally mediated process to remove injured or redundant
cells in a way that preserves nutrients and minimizes inflammation. Necrosis is
an abnormal, uncontrolled process that results in loss of nutrients and
localized or systemic inflammation. Cells can be damaged by a variety of
extrinsic factors causing injuries that can be reversible or irreversible.

Key Points

Billions of cells are created and destroyed
every day

Programmed cell death is a tightly controlled
process to remove senescent, damaged, and nonfunctional cells

Two types of programmed cell death, apoptosis
and autophagy

Necrosis results in death of cells that is not
controlled and does not preserve cellular nutrients

Cells can be injured by a variety of factors,
sometimes resulting in reversible cell injuries and other times producing
irreversible injuries

Programmed cell death is part of an overall
process of adaptation and plasticity of the organ and the organism

Introduction

Cellular and molecular biologists have been uncovering the
mechanisms by which plants and animals attempt to maintain their function at a
cellular level. As cells age they need to be replaced or the organism would quickly
die. The process of cellular death and rebirth is a tightly regulated process
seen in the simplest of multicellular organisms, and dysfunction of that
process can quickly lead to death. An understanding of the processes involved
and abnormalities of those systems can help the dental student better
understand pathological processes in the oral cavity.

Normal Cellular Life Cycle

Approximately 50-70 billion cells die each day in adults.1 Human cells are constantly
dividing, creating new diploid cells with the same or similar function. Cellular
senescence, meaning that cells can no longer divide, occurs after about 50
divisions, eliminating the cumulative effects of errors in copying. These senescent
cells cease to divide but continue to function, adopting senescent phenotypes including
flattened cell morphology and altered gene expression and secretion profiles.2 The accumulation
of senescent cells contributes to the typical age-related phenotypes of the
organism, and senescent cells are more susceptible to effects of starvation,
dehydration, oxidants, and toxins. Of note, the experimental removal of
senescent cells results in removal of the typical age-related phenotype of the
organism and reduces age-related changes seen in older animals.3

Cellular Death

Cells can die in normal or abnormal ways. Programmed cell death is cellular
suicide that is tightly regulated by mitochondria and intracellular molecular signaling
systems. This process is genetically encoded and allows the body to remove
nonfunctional, injured, or redundant cells in an orderly fashion.4 Hypofunction of
this system leads to tumors and metastases5; hyperfunctioning
leads to premature aging. There are two types of programmed cell death:
apoptosis and autophagy. Subtypes and variants of these categories have been
named as well.

Apoptosis is the controlled
self-destruction of a damaged cell. It is an orderly genetically-scripted process
that preserves the nutrients in the cell for later reuse. (See Figure 1.) Apoptosis
is regulated by the mitochondria and is triggered in response to stress such as
the binding of nuclear receptors by glucocorticoids, excessive heat, radiation
exposure, nutrient deprivation, viral infection, hypoxia, and increased
intracellular calcium concentration. In fact increased intracellular calcium concentration
appears to be one of the primary triggers of apoptosis. As has been noted, the
inhibition of apoptosis can result in a number of cancers, autoimmune diseases,
inflammatory diseases, and viral infections.6 In contrast, hyperactive
apoptosis has been linked to certain neurodegenerative diseases, hematologic
diseases, and tissue damage.

Autophagy is a
“housekeeping” process used by cells to clean up intracellular debris. This is
seen as an attempt to repair damaged cells and is important to repair of DNA
fragmentation. In autophagy, a double-walled vacuole called an autophagosome forms
around the debris and fuses with a lysosome, allowing lysosomal enzymes to digest
the vacuolar contents. (See Figure 2.) Under more severe cellular stress,
autophagy removes organelles and protein more rapidly than they can be replaced
and the cell dies. This process allows the recovery of amino acids,
electrolytes, and phospholipids for reuse by new cells.

Necrosis is
another form of cellular turnover that is not part of the programmed cell death
system. Necrosis is an abnormal process that occurs in response to injury, loss
of nutrients, trauma, infection, or exposure to various toxins. (See Figure 3.) In
contrast to programmed cell death, necrosis is not a controlled process and is
seen as being generally detrimental to the organism. In necrosis the cell wall is
disrupted, releasing intracellular contents including digesting lysozymes into the
extracellular fluid resulting in an inflammatory reaction. Because of the
uncontrolled nature of necrosis, the contents of cell are not made available
for recycling.

Repair or Replace

Programmed cell death is seen as an attempt to either repair
damaged cells or replace them with new ones. Organs are in a constant state of
differentiation and plasticity. As new functionality is needed or older
functionality becomes obsolete, cells are destroyed and replaced by either new
cells or stromal cells, the fibrotic scaffolding used by the body to support
other cells. Apoptosis and autophagy are efficient, regulated,
locally-triggered processes that retain amino acids and lipids for use by other
cells. Uncontrolled cellular suicide ultimately leads to the death of the
organism. Impaired apoptosis leads to unchecked cell growth, hyperplasia,
malignancy, and metastases.7 Impairment of
autophagy leads to the accumulation of dysfunctional cells that contain damaged
organelles, organ dysfunction, and premature ageing.8

Cellular Injury

Cells are vulnerable to a variety of injurious factors.
Injury of cells can result in the death of cells, tissue, organ, or the entire organism.
The body is constantly bombarded by toxic molecules causing damage to the
proteins, fats, and DNA of the cell. When cells (and in fact the entire
organism) are young, they are able to repair most cellular damage through a
process of autophagy and self-repair. As the cell ages, the repair process
becomes less efficient, less accurate, and less effective.

Cellular injury can be reversible or irreversible. Reversible
cell injury usually involves injury to the cell wall. This is manifested as cellular
swelling which results in disruption of the sodium-potassium transport pump and
loss of calcium homeostasis. This may be seen in response to hypoxia,
starvation, and hyper- or hypothermia. Cellular swelling is the initial
response to almost every injury and can usually be repaired by removal of the cause
of the insult. As it progresses, cell wall swelling results in an elevated
intracellular calcium which stimulates apoptosis.

Another potentially reversible cell injury is injury to the DNA.
Typically an oxidative stress results in fragmentation of DNA, and the DNA
becomes non-functional or functions abnormally. Glycation is a process of the deposition
of glucose onto DNA, and glycated DNA becomes non-functional or functions
abnormally. This is commonly seen in diabetes mellitus and explains some of the
forms of end-organ damage seen in diabetes including nephropathy, neuropathy,
and microangiopathy. Chemical damage can occur where extrinsic toxins result in
DNA breakage. In general cells try to repair DNA damage and if they are unsuccessful,
apoptosis is triggered.

Irreversible cellular injury includes necrosis. This is a progressive
failure of the essential metabolic and structural cell components, usually
resulting in the death of cells and tissue. Necrotic cells are disrupted and
nonviable, and the only effective treatment requires removal of the necrotic
cells to prevent release of cytotoxins into the organism. An example of
necrosis is gangrene where cells and tissues have died because of lack of
vascular supply. The only effective treatment is excision or debridement back
to viable tissue.

Apoptosis is also considered an irreversible process. This
is the normal turnover of cells that is controlled and results in recovery and
reuse of cellular components. It has been shown that apoptosis can be aborted
locally should conditions change such that the cell no longer needs to die.